Morphological characteristics of motor neurons do not determine their relative susceptibility to degeneration in a mouse model of severe spinal muscular atrophy

Spinal muscular atrophy (SMA) is a leading genetic cause of infant mortality, resulting primarily from the degeneration and loss of lower motor neurons. Studies using mouse models of SMA have revealed widespread heterogeneity in the susceptibility of individual motor neurons to neurodegeneration, but the underlying reasons remain unclear. Data from related motor neuron diseases, such as amyotrophic lateral sclerosis (ALS), suggest that morphological properties of motor neurons may regulate susceptibility: in ALS larger motor units innervating fast-twitch muscles degenerate first. We therefore set out to determine whether intrinsic morphological characteristics of motor neurons influenced their relative vulnerability to SMA. Motor neuron vulnerability was mapped across 10 muscle groups in SMA mice. Neither the position of the muscle in the body, nor the fibre type of the muscle innervated, influenced susceptibility. Morphological properties of vulnerable and disease-resistant motor neurons were then determined from single motor units reconstructed in Thy.1-YFP-H mice. None of the parameters we investigated in healthy young adult mice - including motor unit size, motor unit arbor length, branching patterns, motor endplate size, developmental pruning and numbers of terminal Schwann cells at neuromuscular junctions - correlated with vulnerability. We conclude that morphological characteristics of motor neurons are not a major determinant of disease-susceptibility in SMA, in stark contrast to related forms of motor neuron disease such as ALS. This suggests that subtle molecular differences between motor neurons, or extrinsic factors arising from other cell types, are more likely to determine relative susceptibility in SMA

A cluster randomized controlled trial of the effectiveness and cost-effectiveness of Intermediate Care Clinics for Diabetes (ICCD) : study protocol for a randomized controlled trial

Background World-wide healthcare systems are faced with an epidemic of type 2 diabetes. In the United Kingdom, clinical care is primarily provided by general practitioners (GPs) rather than hospital specialists. Intermediate care clinics for diabetes (ICCD) potentially provide a model for supporting GPs in their care of people with poorly controlled type 2 diabetes and in their management of cardiovascular risk factors. This study aims to (1) compare patients with type 2 diabetes registered with practices that have access to an ICCD service with those that have access only to usual hospital care; (2) assess the cost-effectiveness of the intervention; and (3) explore the views and experiences of patients, health professionals and other stakeholders. Methods/Design This two-arm cluster randomized controlled trial (with integral economic evaluation and qualitative study) is set in general practices in three UK Primary Care Trusts. Practices are randomized to one of two groups with patients referred to either an ICCD (intervention) or to hospital care (control). Intervention group: GP practices in the intervention arm have the opportunity to refer patients to an ICCD - a multidisciplinary team led by a specialist nurse and a diabetologist. Patients are reviewed and managed in the ICCD for a short period with a goal of improving diabetes and cardiovascular risk factor control and are then referred back to practice. or Control group: Standard GP care, with referral to secondary care as required, but no access to ICCD. Participants are adults aged 18 years or older who have type 2 diabetes that is difficult for their GPs to control. The primary outcome is the proportion of participants reaching three risk factor targets: HbA1c (≤7.0%); blood pressure (<140/80); and cholesterol (<4 mmol/l), at the end of the 18-month intervention period. The main secondary outcomes are the proportion of participants reaching individual risk factor targets and the overall 10-year risks for coronary heart disease(CHD) and stroke assessed by the United Kingdom Prospective Diabetes Study (UKPDS) risk engine. Other secondary outcomes include body mass index and waist circumference, use of medication, reported smoking, emotional adjustment, patient satisfaction and views on continuity, costs and health related quality of life. We aimed to randomize 50 practices and recruit 2,555 patients

A Neural Network for Stance Phase detection in smart cane users

Slides from conferencePersons with disabilities often rely on assistive devices to carry on their Activities of Daily Living. Deploying sensors on these devices may provide continuous valuable knowledge on their state and condition. Canes are among the most frequently used assistive devices, regularly employed for ambulation by persons with pain on lower limbs and also for balance. Load on canes is reportedly a meaningful condition indicator. Ideally, it corresponds to the time cane users support weight on their lower limb (stance phase). However, in reality, this relationship is not straightforward. We present a Multilayer Perceptron to reliably predict the Stance Phase in cane users using a simple support detection module on commercial canes. The system has been successfully tested on five cane users in care facilities in Spain. It has been optimized to run on a low cost microcontroller.This work has been supported by: Proyectos Puente and programa operativo de empleo juvenil (UMAJI58) and Plan Propio de Investigación at University of Malaga and the Swedish Knowledge Foundation (KKS) through the research profile Embedded Sensor Systems for Health (ESS−H) at Malardalen University, Sweden. Authors would like to ac- knowledge PONIENTE and LOS NARANJOS senior centers for their support during the tests. Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tec

Predicting mental imagery based BCI performance from personality, cognitive profile and neurophysiological patterns

Mental-Imagery based Brain-Computer Interfaces (MI-BCIs) allow their users to send commands to a computer using their brain-activity alone (typically measured by ElectroEncephaloGraphy— EEG), which is processed while they perform specific mental tasks. While very promising, MI-BCIs remain barely used outside laboratories because of the difficulty encountered by users to control them. Indeed, although some users obtain good control performances after training, a substantial proportion remains unable to reliably control an MI-BCI. This huge variability in user-performance led the community to look for predictors of MI-BCI control ability. However, these predictors were only explored for motor-imagery based BCIs, and mostly for a single training session per subject. In this study, 18 participants were instructed to learn to control an EEG-based MI-BCI by performing 3 MI-tasks, 2 of which were non-motor tasks, across 6 training sessions, on 6 different days. Relationships between the participants’ BCI control performances and their personality, cognitive profile and neurophysiological markers were explored. While no relevant relationships with neurophysiological markers were found, strong correlations between MI-BCI performances and mental-rotation scores (reflecting spatial abilities) were revealed. Also, a predictive model of MI-BCI performance based on psychometric questionnaire scores was proposed. A leave-one-subject-out cross validation process revealed the stability and reliability of this model: it enabled to predict participants’ performance with a mean error of less than 3 points. This study determined how users’ profiles impact their MI-BCI control ability and thus clears the way for designing novel MI-BCI training protocols, adapted to the profile of each user

Diffuse Alveolar Hemorrhage

This article is made available for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.Diffuse alveolar hemorrhage[DAH] is a serious condition that can be life threatening. It can be caused by a constellation of disorders which presents with hemoptysis, anemia, and diffuse alveolar infiltrates. Respiratory failure from DAH can be so severe that it has been called an ARDS mimic/imitator. Early recognition is crucial because prompt diagnosis and treatment are required for survival. DAH should be distinguished from other causes of pulmonary hemorrhage caused by localized pulmonary abnormalities and the bronchial circulation. Early bronchoscopy with bronchoalveolar lavage (BAL) is generally required to confirm the diagnosis of DAH and rule out infection. Progressively bloody bronchoalveolar lavage samples can distinguish DAH. Systemic vasculitis is one of the most common causes of DAH and can be pathologically defined by the presence of cellular inflammation, vessel destruction, tissue necrosis, and eventually, organ dysfunction. Corticosteroids and immunosuppressive agents remain the gold standard for the treatment. The following case illustrates a patient who was dependent on dialysis, then presented with hemoptysis. Bronchoscopy demonstrated progressively bloody bronchoalveolar lavage samples consistent with diffuse alveolar hemorrhage. Serologic testing was consistent with microscopic polyangiitis. The patient experienced a clinical remission with cyclophosphamide and corticosteroids

Macrocyclic colibactin induces DNA double-strand breaks via copper-mediated oxidative cleavage.

Colibactin is an assumed human gut bacterial genotoxin, whose biosynthesis is linked to the clb genomic island that has a widespread distribution in pathogenic and commensal human enterobacteria. Colibactin-producing gut microbes promote colon tumour formation and enhance the progression of colorectal cancer via cellular senescence and death induced by DNA double-strand breaks (DSBs); however, the chemical basis that contributes to the pathogenesis at the molecular level has not been fully characterized. Here, we report the discovery of colibactin-645, a macrocyclic colibactin metabolite that recapitulates the previously assumed genotoxicity and cytotoxicity. Colibactin-645 shows strong DNA DSB activity in vitro and in human cell cultures via a unique copper-mediated oxidative mechanism. We also delineate a complete biosynthetic model for colibactin-645, which highlights a unique fate of the aminomalonate-building monomer in forming the C-terminal 5-hydroxy-4-oxazolecarboxylic acid moiety through the activities of both the polyketide synthase ClbO and the amidase ClbL. This work thus provides a molecular basis for colibactin's DNA DSB activity and facilitates further mechanistic study of colibactin-related colorectal cancer incidence and prevention

The evaluation of a healthcare passport to improve quality of care and communication for people living with dementia (EQuIP): a protocol paper for a qualitative, longitudinal study

Background\ud \ud There is an urgent need for the development of simple communication tools that convey the strengths, assets, and healthcare needs of people living with dementia. A Healthcare Passport may improve communication with range of health and social support services, enhancing quality and continuity of care, and to permit a consideration of the challenges and how these might be managed effectively and compassionately. This study aims to evaluate the acceptability and use of this type of intervention for people living with dementia and their carers.\ud \ud \ud Methods/Design\ud \ud This is a qualitative longitudinal study informed by a critical realist review. The participants will be individuals identified as having mild-moderate dementia and informal carers. The in-depth interviews will occur at three points over the course of 18 months as they use the passport. This will be supplemented by analysis of the content of the passports and information from health and social care providers on the daily practicalities of using the passport in a range of healthcare settings.\ud \ud \ud Discussion\ud \ud By using a critical realist review and a qualitative, longitudinal approach, the study allows for the assessment of a complex intervention in a manner which goes beyond evaluating the basic efficacy of the passport, but looking more deeply at how it worked, for whom, and in what context. It has the potential to develop new data on how interventions improve communication across a range of service providers, while encouraging health and social care professionals to respect and encourage the development of self-management and retention of personhood throughout the progression of life-limiting illnesses

Molecular and cellular mechanisms underlying the evolution of form and function in the amniote jaw.

The amniote jaw complex is a remarkable amalgamation of derivatives from distinct embryonic cell lineages. During development, the cells in these lineages experience concerted movements, migrations, and signaling interactions that take them from their initial origins to their final destinations and imbue their derivatives with aspects of form including their axial orientation, anatomical identity, size, and shape. Perturbations along the way can produce defects and disease, but also generate the variation necessary for jaw evolution and adaptation. We focus on molecular and cellular mechanisms that regulate form in the amniote jaw complex, and that enable structural and functional integration. Special emphasis is placed on the role of cranial neural crest mesenchyme (NCM) during the species-specific patterning of bone, cartilage, tendon, muscle, and other jaw tissues. We also address the effects of biomechanical forces during jaw development and discuss ways in which certain molecular and cellular responses add adaptive and evolutionary plasticity to jaw morphology. Overall, we highlight how variation in molecular and cellular programs can promote the phenomenal diversity and functional morphology achieved during amniote jaw evolution or lead to the range of jaw defects and disease that affect the human condition

Organometallic palladium reagents for cysteine bioconjugation

Reactions based on transition metals have found wide use in organic synthesis, in particular for the functionalization of small molecules. However, there are very few reports of using transition-metal-based reactions to modify complex biomolecules, which is due to the need for stringent reaction conditions (for example, aqueous media, low temperature and mild pH) and the existence of multiple reactive functional groups found in biomolecules. Here we report that palladium(II) complexes can be used for efficient and highly selective cysteine conjugation (bioconjugation) reactions that are rapid and robust under a range of bio-compatible reaction conditions. The straightforward synthesis of the palladium reagents from diverse and easily accessible aryl halide and trifluoromethanesulfonate precursors makes the method highly practical, providing access to a large structural space for protein modification. The resulting aryl bioconjugates are stable towards acids, bases, oxidants and external thiol nucleophiles. The broad utility of the bioconjugation platform was further corroborated by the synthesis of new classes of stapled peptides and antibody–drug conjugates. These palladium complexes show potential as benchtop reagents for diverse bioconjugation applications.National Institutes of Health (U.S.) (GM-58160)National Institutes of Health (U.S.) (GM-101762)MIT Faculty Start-up FundDamon Runyon Cancer Research FoundationSontag Foundation (Distinguished Scientist Award)Massachusetts Institute of Technology. Dept. of Chemistry (George Buchi Research Fellowship)David H. Koch Institute for Integrative Cancer Research at MIT (Graduate Fellowship in Cancer Research

The expression of p53-induced protein with death domain (Pidd) and apoptosis in oral squamous cell carcinoma

The Pidd (p53-induced protein with death domain) gene was shown to be induced by the tumour suppressor p53 and to mediate p53-dependent apoptosis in mouse and human cells, through interactions with components of both the mitochondrial and the death receptor signalling pathways. To study the role of Pidd in clinical tumours, we measured its expression by quantitative reverse transcription-PCR in microdissected oral squamous cell carcinomas (OSCC) with and without p53 mutation. Tumour cell apoptosis was assessed by in situ terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling. Tumour proliferation was assessed by immunohistochemical staining for the Ki-67 antigen. We found a wide range of Pidd expression among OSCC. Statistical analysis revealed an association between Pidd expression and apoptotic index (Mann–Whitney test, P<0.001), consistent with a role of Pidd in apoptosis in this tumour type. Furthermore, we showed a positive correlation between apoptotic index and proliferative index that has not been previously described for OSCC. There was no correlation between Pidd expression and the p53 mutation status of these tumours, suggesting that Pidd expression may be regulated by p53-independent mechanisms. Further characterisation of these molecular defects in the control of proliferation and apoptosis should help in developing treatments that target OSCC according to their biological properties